2.1. STERIC RELATIONSHIPS AND DRUG ACTION
Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (-) or d and 1 are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Stereochemical purity is of importance in the field of pharmaceuticals, where 16 of the 20 most prescribed drugs exhibit chirality. A case in point is provided by the L-form of the .beta. -adrenergic blocking agent, propranolol, which is known to be 100 times more potent than the D-enantiomer.
Furthermore, optical purity is important-since certain isomers may actually be deleterious rather than simply inert. For example, it has been suggested that the D-enantiomer of thalidomide was a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, while the corresponding L-enantiomer was a potent teratogen.
Bupropion is available only as a racemic mixture called Wellbutrin.RTM. and Wellbutrin SR.RTM. (for depression), and Zyban|.RTM. (to achieve smoking-cessation). That is, bupropion is available as a mixture of optical isomers, called enantiomers. The racemic mixture of bupropion which is commercially available is administered as a hydrochloride salt. In addition, European Patent Application No. 84101070.5 published Sep. 12, 1984 discloses the benefits of bupropion maleate over bupropion hydrochloride.
Bupropion is used primarily in the treatment-of depression, which along with mania, falls under the heading of affective disorders. Particularly, bupropion is used in patients who do not respond to, or cannot tolerate other antidepressants, such as the tricyclic agents or monoamine oxidase inhibitors. Additionally, the racemic mixture of bupropion is useful in the management of patients with bipolar and schizo-affective disorder, attention-deficit disorder, psycho-sexual dysfunction, bulimia and-other eating disorders, and Parkinson's disease.
Affective disorders, including major depression, and the bipolar, manic-depressive illness, are characterized by changes in mood as the primary clinical manifestation. Major depression is the most common of the significant mental illnesses, and it must be distinguished clinically from periods of normal grief, sadness and disappointment, and the related dysphoria or demoralization frequently associated with medical illness. Depression is characterized by feelings of intense sadness, and despair, mental slowing and loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical changes can also occur, including insomnia, anorexia, and weight loss, decreased energy and libido, and disruption of hormonal circadian rhythms. Often the condition responds well to tricyclic or related antidepressant drugs, monoamine oxidase inhibitors, or in resistant cases or severe disease, to electro-convulsive shock treatment.
Mania, as well as depression, is characterized by changes in mood as the primary symptom. Either of these two extremes of mood may be accompanied by psychosis with disordered thought and delusional perceptions. Psychosis may have, as a secondary symptom, a change in mood, and it is this overlap with depression that causes much confusion in diagnosis. Severe mood changes without psychosis frequently occur in depression and are often accompanied by anxiety.
Through an unknown mechanism of action, bupropion has been demonstrated to be an effective treatment in depression in short-term and longer duration clinical studies. The racemic mixture of bupropion has been reported to have an antidepressant activity equal to amitriptyline, the tricyclic antidepressant, with fewer anticholinergic, sedative and cardiovascular side effects than with amitriptyline.
Parkinson's disease, independent of a specific etiology, is a chronic, progressive central nervous system disorder which usually appears insidiously in the latter. decades of life. The disease produces a slowly increasing disability in purposeful movement. It is characterized by four major clinical features of tremor, bradykinesia, rigidity and a disturbance of posture. Often patients have an accompanying dementia. In idiopathic Parkinsonism, there is usually a loss of cells in the substantia nigra, locus ceruleus, and other pigmented neurons of the brain, and a decrease of dopamine content in nerve axon terminals of cells projecting from the substantia nigra. The understanding that Parkinsonism is a syndrome of dopamine deficiency and the discovery of levodopa as an important drug for the treatment of the disease were the logical culmination of a series of related basic and clinical observations, which serves as the rationale for drug treatment.
When the racemic mixture of bupropion is used to treat Parkinson's disease, an improvement in gait, akinesia, and postural stability were observed, with tremor improving in those patients experiencing the most global benefit. Concomitant depression was alleviated in several of the patients reporting the condition.
Attention-deficit disorder ("ADD") is a common behavioral learning disorder in children which adversely affects school performance and family relationships. Symptoms and signs include hyperactivity (e.g., ADDH and AD/HD, DSM-IV), impulsivity, emotional lability, motor incoordination and some perceptual difficulties. Treatment has included psychostimulants, which while effective are controversial, and may cause troubling side effects such as dysphoria, headache and growth retardation. Other drugs, including the tricyclic antidepressants, appear to improve attention, but may be less effective than the psychostimulants.
Bupropion has been shown to be effective in children with attention-deficit disorder or conduct disorder thus improving the symptoms of anxiety, hostility and uncooperativeness, antisocial behavior, as well as eating disturbances. The drug has also demonstrated activity in cases of psycho-sexual dysfunction and bulimia. However, bupropion is contra-indicated in patients with a seizure disorder, or a current or prior diagnosis of bulimia or anorexia nervosa characterized by a disturbed sense of body image and abnormally high anxiety about weight gain.
It has been suggested that the racemic mixture of bupropion could be used to assist in weight loss. Treatment with bupropion is consistently associated with a lack of weight gain. Also bupropion reduces episodes of.binge eating and purging. Although the mechanism by which buprop'ion causes weight loss is uncertain, an increase in the activity of the patient may play some part together with subtle changes in food intake and metabolism.
The causes of excess body weight and/or obesity are complex; however, a common denominator in the overweight person's diet is a caloric intake which exceeds that person's body expenditures. One method of treating a person who is overweight and/or obese is to restrict that person's caloric intake, in combination with an exercise regimen. This method may be limited in its effectiveness since many overweight or obese people have developed eating and activity patterns which are counterproductive to achieving weight reduction. Another method to treat overweight or obese patients is to administer appetite suppressant drugs in conjunction with a weight reduction program. The drawback to this method is that many appetite suppressant drugs produce undesirable adverse effects which limit their usefulness.
The racemic mixture of bupropion, in addition to its use in the treatment of depression and the other above-mentioned disorders, has been shown to have a wide spectrum of action which includes:
Treatment of the effects of ethanol (U.S. Pat. No. 4,393,078) PA1 Treatment of Tardine Dyskinesia (U.S. Pat. No. 4,425,363) PA1 Treatment of Minimal Brain Dysfunction (U.S. Pat. No. 4,435,449) PA1 Treatment of amelioration of prostate hypertrophy and sexual dysfunction (U.S. Pat. No. 4,835,147) PA1 Treatment of psychostimulant addiction (U.S. Pat. No. 4,935,429) PA1 Treatment of Psychosexual Dysfunction (U.S. Pat. No. 4,507,323) PA1 Methods of Reducing Cholesterol (U.S. Pat. No. 4,438,138) PA1 Methods of assisting weight loss (U.S. Pat. No. 4,895,845)
The racemic mixture of bupropion has been shown to have certain advantages over other antidepressant drugs. For example, bupropion does not inhibit monoamine oxidase, or block the reuptake of serotonin. At therapeutic concentrations, the compound presumably does not bind to adrenergic, dopamine, GABA, histamine, muscarinic, serotonin, or imipramine binding sites. While its specific neurochemical antidepressant action is unknown, it does have a relatively weak effect on blocking the reuptake of dopamine, and it appears to reduce norepinephrine metabolism.
While the racemic mixture of bupropion has advantages,. it also has disadvantages. Among these disadvantages are adverse effects in addition to those described above. The most serious adverse effect associated with the racemic mixture of bupropion is the increased incidence of seizures. In addition, other frequently reported adverse effects associated with the use of racemic bupropion include nausea, vomiting, excitement, agitation, blurred vision, restlessness, postural tremor, and some hallucinations/confusional states with the potential for abuse. Other adverse or side effects associated with the racemic mixture of bupropion include but are not-limited to anxiety, insomnia, headaches and/or migraines, dry mouth, constipation, tremor, sleeping disturbances, dermatologic problems (e.g., rashes), neuropsychiatric signs and symptoms (e.g.; delusions and paranoia), and weight loss gain. See, the Physician's. Desk References.RTM. (1998). These effects are dose limiting in a number of patients. In Parkinsonian patients, the adverse effects can be the particular toxicity of the racemic mixture of bupropion, or the result of a drug interaction (as most patients were receiving concomitant levodopa).
Thus, it is desirable to find a compound with the advantages of the racemic mixture of bupropion without the above-described disadvantages.